Astrocytic GABA Transporter controls sleep by modulating GABAergic signaling in Drosophila circadian neurons

A precise balance between sleep and wakefulness is essential to sustain a good quality of life and optimal brain function. GABA is known to play a key and conserved role in sleep control, and GABAergic tone should therefore be tightly controlled in sleep circuits. Here we examined the role of the astrocytic GABA transporter (GAT) in sleep regulation using Drosophila melanogaster. We found that a hypomorphic gat mutation (gat33-1) increased sleep amount, decreased sleep latency, and increased sleep consolidation. Interestingly, sleep defects were suppressed when gat33-1 was combined with a mutation disrupting wide-awake (wake), a gene that regulates the cell-surface levels of the GABAA receptor Resistance to Dieldrin (RDL) in the wake-promoting large ventral lateral neurons (l-LNvs). Moreover, RNAi knockdown of rdl and its modulator dnlg4 in these circadian neurons also suppressed gat33-1 sleep phenotypes. Brain immunohistochemistry showed that GAT-expressing astrocytes were located near RDL-positive l-LNvs cell bodies and dendritic processes. We conclude that astrocytic GAT decreases GABAergic tone and RDL activation in arousal promoting LNvs, thus determining proper sleep amount and quality in Drosophila

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The truncated TrkB receptor influences mammalian sleep

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00422.2014 ◽

2015 ◽

Vol 308 (3) ◽

pp. R199-R207 ◽

Cited By ~ 8

Author(s):

Adam J. Watson ◽

Kyle Henson ◽

Susan G. Dorsey ◽

Marcos G. Frank

Keyword(s):

Rem Sleep ◽

Knockout Mice ◽

Psychiatric Illness ◽

Sleep Latency ◽

Sleep Time ◽

Sleep Regulation ◽

Trkb Receptor ◽

Adult Mice ◽

The Relationship

Brain-derived neurotrophic factor (BDNF) is a neurotrophin hypothesized to play an important role in mammalian sleep expression and regulation. In order to investigate the role of the truncated receptor for BDNF, TrkB.T1, in mammalian sleep, we examined sleep architecture and sleep regulation in adult mice constitutively lacking this receptor. We find that TrkB.T1 knockout mice have increased REM sleep time, reduced REM sleep latency, and reduced sleep continuity. These results demonstrate a novel role for the TrkB.T1 receptor in sleep expression and provide new insights into the relationship between BDNF, psychiatric illness, and sleep.

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Dominant Role of the Gut Microbiota in Chemotherapy Induced Neuropathic Pain

Scientific Reports ◽

10.1038/s41598-019-56832-x ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 12

Author(s):

Chandran Ramakrishna ◽

Jose Corleto ◽

Paul M. Ruegger ◽

Geoffrey D. Logan ◽

Beth B. Peacock ◽

...

Keyword(s):

Gut Microbiota ◽

Patient Outcomes ◽

Brain Function ◽

Pain Sensitivity ◽

Dominant Role ◽

Systemic Exposure ◽

Cancer Treatments ◽

Toxic Side Effect

AbstractChemotherapy induced peripheral neuropathy (CIPN), a toxic side effect of some cancer treatments, negatively impacts patient outcomes and drastically reduces survivor’s quality of life (QOL). Uncovering the mechanisms driving chemotherapy-induced CIPN is urgently needed to facilitate the development of effective treatments, as currently there are none. Observing that C57BL/6 (B6) and 129SvEv (129) mice are respectively sensitive and resistant to Paclitaxel-induced pain, we investigated the involvement of the gut microbiota in this extreme phenotypic response. Reciprocal gut microbiota transfers between B6 and 129 mice as well as antibiotic depletion causally linked gut microbes to Paclitaxel-induced pain sensitivity and resistance. Microglia proliferated in the spinal cords of Paclitaxel treated mice harboring the pain-sensitive B6 microbiota but not the pain-resistant 129 microbiota, which exhibited a notable absence of infiltrating immune cells. Paclitaxel decreased the abundance of Akkermansia muciniphila, which could compromise barrier integrity resulting in systemic exposure to bacterial metabolites and products – that acting via the gut-immune-brain axis – could result in altered brain function. Other bacterial taxa that consistently associated with both bacteria and pain as well as microglia and pain were identified, lending support to our hypothesis that microglia are causally involved in CIPN, and that gut bacteria are drivers of this phenotype.

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Depression and Cardiovascular Disease: The Viewpoint of Platelets

International Journal of Molecular Sciences ◽

10.3390/ijms21207560 ◽

2020 ◽

Vol 21 (20) ◽

pp. 7560

Author(s):

Patrizia Amadio ◽

Marta Zarà ◽

Leonardo Sandrini ◽

Alessandro Ieraci ◽

Silvia Stella Barbieri

Keyword(s):

Cardiovascular Disease ◽

Platelet Activation ◽

Brain Function ◽

Critical Role ◽

Major Adverse Cardiovascular Events ◽

Cardiac Events ◽

The Relationship ◽

The Brain

Depression is a major cause of morbidity and low quality of life among patients with cardiovascular disease (CVD), and it is now considered as an independent risk factor for major adverse cardiovascular events. Increasing evidence indicates not only that depression worsens the prognosis of cardiac events, but also that a cross-vulnerability between the two conditions occurs. Among the several mechanisms proposed to explain this interplay, platelet activation is the more attractive, seeing platelets as potential mirror of the brain function. In this review, we dissected the mechanisms linking depression and CVD highlighting the critical role of platelet behavior during depression as trigger of cardiovascular complication. In particular, we will discuss the relationship between depression and molecules involved in the CVD (e.g., catecholamines, adipokines, lipids, reactive oxygen species, and chemokines), emphasizing their impact on platelet activation and related mechanisms.

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029 Median preoptic dual control over sleep regulation

SLEEP ◽

10.1093/sleep/zsab072.028 ◽

2021 ◽

Vol 44 (Supplement_2) ◽

pp. A13-A14

Author(s):

Natalia Machado ◽

William Todd ◽

Clifford Saper

Keyword(s):

Nrem Sleep ◽

Underlying Mechanism ◽

Brain Regions ◽

Sleep Cycle ◽

Sleep Regulation ◽

Sleep Behavior ◽

Sleep Homeostasis ◽

Psychological Stressor ◽

Sleep Control

Abstract Introduction Previous studies suggest that the median preoptic nucleus (MnPO) plays an important role in regulating the wake-sleep cycle and in particular homeostatic sleep drive. However, the precise cellular phenotypes, targets and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both glutamatergic (Vglut2+) and GABAergic (Vgat+) MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate on sleep control. Methods In this study, we used two genetically-targeted approaches associated with electroencephalographic (EEG) and electromyographic (EMG) recordings in Vgat-IRES-cre and Vglut2-IRES-cre mice to investigate the role of the MnPOVgat and MnPOVglut2 neurons in modulating wake-sleep behavior. Results First, using a chemogenetic approach, we found that activation of MnPOVgat neurons reduced the latency for the first NREM sleep episode, produced an increase in NREM sleep and reduced wakefulness. Then, to test the role of MnPOVgat and MnPOVglut2 neurons in regulating sleep homeostasis, we recorded EEG and EMG responses in mice that had the Vgat+ or Vglut2+ neurons deleted from the MnPO. After deletion of MnPOVgat neurons, mice showed a reduction of NREM sleep and an increase in wakefulness during the light phase. Deletion of MnPOVgat neurons also reduced sleep recovery after 4 hours of sleep deprivation (SD). On the other hand, deletion of the MnPOVglut2 neurons did not change the wake-sleep cycle during the 24h baseline condition, but prevented the sleep recovery immediately after SD. To understand the underlying mechanism in preventing sleep recovery in both MnPOVglut2- and MnPOVgat-deleted mice groups, we exposed these animals to a psychological stress protocol. In response to a psychological stressor, mice with deletion of glutamatergic, but not GABAergic MnPO neurons, had an exacerbation of the stress-induced insomnia. Conclusion Our results suggest that both neuron populations differentially participate in wake-sleep control, with MnPOVgat neurons being critically involved in sleep homeostasis, and MnPOVglut2 neurons promoting sleep during allostatic (stressful) challenges. Support (if any) NIH Grants NS085477, NS072337, HL095491 and Sleep Research Society Foundation (Award 026-JP-20).

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Cognitive Health Counseling 40+

Zeitschrift für Gesundheitspsychologie ◽

10.1026/0943-8149/a000085 ◽

2013 ◽

Vol 21 (1) ◽

pp. 24-33 ◽

Cited By ~ 1

Author(s):

Anne Eschen ◽

Franzisca Zehnder ◽

Mike Martin

Keyword(s):

Outcome Variable ◽

Pilot Phase ◽

Subjective Memory ◽

Cognitive Health ◽

Health Counseling ◽

Agents Of Change ◽

Main Outcome Variable ◽

Further Development

This article introduces Cognitive Health Counseling 40+ (CH.CO40+), an individualized intervention that is conceptually based on the orchestration model of quality-of-life management ( Martin & Kliegel, 2010 ) and aims at improving satisfaction with cognitive health in adults aged 40 years and older. We describe the theoretically deduced characteristics of CH.CO40+, its target group, its multifactorial nature, its individualization, the application of subjective and objective measures, the role of participants as agents of change, and the rationale for choosing participants’ satisfaction with their cognitive health as main outcome variable. A pilot phase with 15 middle-aged and six older adults suggests that CH.CO40+ attracts, and may be particularly suitable for, subjective memory complainers. Implications of the pilot data for the further development of the intervention are discussed.

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